EP3441106A2 - Mikronadelstruktur zur effizienten hautperforation - Google Patents
Mikronadelstruktur zur effizienten hautperforation Download PDFInfo
- Publication number
- EP3441106A2 EP3441106A2 EP17779345.2A EP17779345A EP3441106A2 EP 3441106 A2 EP3441106 A2 EP 3441106A2 EP 17779345 A EP17779345 A EP 17779345A EP 3441106 A2 EP3441106 A2 EP 3441106A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- microneedle
- skin
- present disclosure
- target material
- smaller
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/23—Carbohydrates
- A61L2300/232—Monosaccharides, disaccharides, polysaccharides, lipopolysaccharides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0023—Drug applicators using microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0046—Solid microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0061—Methods for using microneedles
Definitions
- the present disclosure relates to a soluble microneedle, particularly to a microneedle used to perforate skin which, when inserted through the perforated skin, is dissolved, thereby administering a target material inside the microneedle into the skin.
- the microneedle microfile, micromissile capsule, etc.
- the microneedle is made of metals, silicone, etc., self-degradable materials or biodegradable materials.
- the microneedle has the characteristic that it can be inserted into the skin without pain or bleeding. However, it is very difficult to make a microneedle which satisfies this characteristic and, at the same time, does not bend or break.
- the shape change and perforation rate of the microneedle are principal factors that directly affect the skin permeation rate of the microneedle and the ultimate delivery of the target material. Therefore, there is a consistent need for development of a microneedle in consideration of these factors.
- the present disclosure is directed to providing a microneedle, which exhibits high skin perforation rate and skin permeation rate without having to apply strong force and is capable of effectively delivering a target material into the skin regardless of which part of the microneedle it is contained, and a microneedle patch containing the same.
- the present disclosure provides a soluble microneedle having one or more of the following features:
- soluble microneedle having the following features:
- soluble microneedle having one or more of the following features:
- soluble microneedle having the following features:
- the present disclosure also provides a microneedle patch containing two or more of the microneedle (specifically soluble microneedle) and a support holding the soluble microneedle.
- a ratio of the size of the microneedle to the distance between the microneedles may be greater than 0.1 and equal to or smaller than 2, specifically 0.5-2.
- microneedles have the problem that, when inserted into the skin by compressing with a hand, the target material is hardly delivered because they are bent. Others are inconvenient to use because they cannot perforate the skin with normal force. If strong pressure is applied to ensure perforation, it leads to breakage of the microneedle or pain. Also, if the microneedle is not sufficiently dissolved in the perforated skin, the target material contained in the microneedle closer to the support of the microneedle remains without being provided to the skin.
- the inventors of the present disclosure have studied for a long time and have developed a microneedle and a microneedle patch capable of solving all the problems described above and achieving high skin perforation rate and skin permeation rate by controlling the physical properties of the microneedle, particularly the tip diameter of the microneedle, the aspect ratio of the microneedle and the density of the microneedle in the patch.
- the skin refers to the surface of a body contacting the external environment.
- the skin includes the cornea, oral soft tissue, gingiva, nasal mucosa, etc.
- the application to the skin refers to adhesion, attachment or, specifically, insertion to the skin surface for transdermal administration.
- FIGS. 1A and 1B are electron microscopic images of a microneedle fabricated according to an exemplary embodiment of the present disclosure.
- FIG. 1A shows a plurality of microneedles formed on the surface of a microneedle support.
- the microneedles protruding from the microneedle support may form, for example, a microneedle patch.
- the microneedles protrude from the microneedle support.
- the microneedle may have a tapered shape.
- the microneedle is extended away from the support surface as it is tapered from the base of the microneedle toward the tip surface.
- ' l ' means the distance between the microneedles.
- FIG. 1B shows the enlarged structure of the microneedle formed on the support surface.
- ' h ' means the height of the microneedle.
- ' m ' means the bottom side of the longitudinal section of the microneedle and
- ' d ' means the diameter of the microneedle.
- FIG. 2 shows a microneedle 10 with a shape of a tetragonal pyramid having four bottom sides according to an exemplary embodiment of the present disclosure.
- FIG. 2(a) shows a microneedle 10 with a shape of a tetragonal pyramid having four bottom sides
- the microneedle may have any appropriate shapes such as a trigonal pyramid, etc.
- the pyramidal microneedle may have a shape of an equilateral pyramid or not.
- the microneedle 10 may be a truncated pyramid having a tip surface which may be flat, rather than a perfect pyramid.
- the truncated pyramid may refer to a pyramid obtained by truncating the sharp tip of the pyramid where all the side faces meet together.
- the tip surface 11 may be located on a plane which is parallel to the bottom side m of the microneedle. Alternatively, the tip surface 11 may be located on a plane which is not parallel to the base 21.
- the diameter of the tip surface 11 may be designated as d.
- the longest side of the tetragonal tip surface is designated as ' d ' for convenience's sake. However, it may be understood to mean the diameter of a circle having the same area as that of the tip surface.
- the bottom side m of the microneedle' may be understood to mean the diameter of a circle having the same area as that occupied by the microneedle base 21 on the support 20.
- the tip surface 11 does not need to be perfectly flat.
- the tip surface 11 may be slightly modified from a completely flat surface but, even in that case, it can be called flat in the context of the present disclosure.
- the microneedle according to the present disclosure is tapered from the wide base adjacent to the support toward the narrow tip surface.
- FIG. 3 shows that the tapered microneedle 30 is not necessarily restricted to the pyramidal shape.
- a microneedle patch 200 of the present disclosure may be one wherein one or a plurality of conical microneedle(s) 30 is(are) formed on a microneedle support 40.
- the microneedle patch may be one wherein a plurality of conical microneedles and a plurality of truncated pyramidal microneedles, which are tapered, are arranged on the support of the microneedle patch.
- an exemplary embodiment of the present disclosure may provide a conical microneedle 30 formed on a support 40 of a microneedle patch 200.
- the area of the conical microneedle 30 occupied by a base 32 may have a circular shape.
- the base 32 may also have different shapes, such as oval, elongated circular or crescent shapes.
- the microneedle is shown to have an equilateral conical shape, the conical microneedle of the present disclosure is not necessarily restricted to the equilateral conical shape.
- the bottom side m of the microneedle' of the present disclosure may be understood to mean the diameter of a circle having the same area as that occupied by the microneedle base 32 on the support 20.
- the microneedle is a truncated cone which is truncated at the tip surface 31 which is parallel to the base 32 adjacent to the support surface 41.
- the tip surface 31 may be located on a plane which is parallel to the base 32 of the microneedle 30. Alternatively, the tip surface 31 may be located on a plane which is not parallel to the base 32.
- the tip surface 31 does not need to be perfectly flat.
- the tip surface 31 may be slightly modified from a completely flat surface but, even in that case, it can be called flat in the context of the present disclosure.
- the 'tip' refers to the end of the microneedle which contacts the skin first when the microneedle is applied to the skin.
- the 'tip surface' refers to the area occupied by the tip when the microneedle is seen from above with the base at the bottom.
- the 'tip diameter' means the diameter of the circle.
- the tip surface has a tetragonal shape, it means the diameter of a circle having the same area as that of the tip surface.
- a 'cross section' refers to the section cut along a horizontal direction.
- the shape of the cross section may be various depending on the type of the microneedle.
- the cross section of the microneedle according to an exemplary embodiment of the present disclosure may have a tetragonal or circular shape, although not being limited thereto.
- the tip diameter may be 20 ⁇ m or smaller, specifically 19 ⁇ m or smaller, 18 ⁇ m or smaller, 17 ⁇ m or smaller, 16 ⁇ m or smaller, 15 ⁇ m or smaller, 14 ⁇ m or smaller, 13 ⁇ m or smaller, 12 ⁇ m or smaller, 11 ⁇ m or smaller, 10 ⁇ m or smaller, 9 ⁇ m or smaller, 8 ⁇ m or smaller, 7 ⁇ m or smaller, 6 ⁇ m or smaller, 5 ⁇ m or smaller, 4 ⁇ m or smaller, 3 ⁇ m or smaller, 2 ⁇ m or smaller, 1 ⁇ m or smaller, or 0.5 ⁇ m or smaller, most specifically 0.1-10 ⁇ m.
- the microneedle may more effectively perforate the skin when the tip diameter is 20 ⁇ m or smaller.
- an 'aspect ratio' refers to a ratio of the height of the microneedle to its bottom side.
- the 'height h' or 'needle size' refers to the total length of the microneedle, or the linear distance from the tip surface to the base of the microneedle. It can be determined by measuring the height from the longitudinal section of the microneedle.
- the height of the microneedle according to an exemplary embodiment of the present disclosure may be referred to in FIG. 1B , although not being limited thereto.
- the 'bottom side m ' or 'needle base' may be determined by measuring the bottom side length from the longitudinal section of the microneedle.
- the 'longitudinal section' refers to the section cut along a longitudinal direction.
- the longitudinal section of the microneedle may refer to a section passing through the center of gravity of the microneedle and the center of the tip surface.
- the longitudinal section of the microneedle according to an exemplary embodiment of the present disclosure may be referred to in FIG. 1B , although not being limited thereto.
- the aspect ratio may be 1-5, specifically 1.5-3. If the aspect ratio is smaller than 1, skin perforation may be difficult because the microneedle is blunt. And, if it exceeds 5, skin perforation may be difficult because the microneedle is broken or bent easily.
- the microneedle according to the present disclosure may have a compressive yield strength (compressive force / area of microneedle tip) of 10 kN/cm 2 or higher.
- the microneedle is effective for skin perforation when the compressive yield strength is 10 kN/cm 2 or higher.
- the area of the microneedle refers to the area of the microneedle tip surface.
- the microneedle according to the present disclosure is not restricted to a specific shape and any shape that is commonly recognized as a microneedle, a microfile, a micromissile capsule, etc. can be included in the scope of the present disclosure. Specifically, it may have a shape which becomes narrower toward the end of the microneedle, e.g., a cone, a polygonal pyramid (trigonal pyramid, quadrangular pyramid, etc.), a combination of a cylinder and a cone, etc., although not being limited thereto.
- the microneedle according to the present disclosure may have indentation, unevenness, spiral, etc. on its surface.
- the microneedle according to the present disclosure may be made of a general synthetic or natural polymer. Specifically, a water-soluble polymer or a self-degradable or biodegradable material may be used.
- hyaluronic acid sodium carboxymethyl cellulose, a vinylpyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, polyvinylpyrrolidone, a saccharide or a mixture thereof may be used, for example.
- saccharide xylose, sucrose, maltose, lactose, trehalose or a mixture thereof may be used.
- hyaluronic acid, sodium carboxymethyl cellulose and a saccharide may be used.
- a composition for preparing the microneedle may contain 1-60 wt% of sodium carboxymethyl cellulose, 1-60 wt% of hyaluronic acid and 3-60 wt% of a saccharide based on the total weight.
- the saccharide may be trehalose.
- the microneedle according to the present disclosure may further contain a solubilizer, a plasticizer, a surfactant, a preservative, an anti-inflammatory agent, etc.
- a plasticizer a polyol such as ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, glycerin, etc. may be used alone or in combination, for example. More specifically, glycerin may be used when considering the result of various evaluations.
- the solubilizer various ingredients known in the art can be adequately selected and used. Specifically, HCO-40 may be used when considering the result of various evaluations of the physical properties and durability of the microneedle and compatibility with other materials forming the microneedle.
- microneedle according to the present disclosure may further contain additional ingredients for achieving synergistic effects depending on the target material.
- the microneedle according to the present disclosure may optionally contain various target materials.
- the target material may be, for example, a drug, a vaccine, a nutrient or a cosmetic ingredient.
- a cell, a protein, a nucleic acid, a peptide, a polysaccharide, a lipid, etc. may be contained depending on use.
- niacinamide may be used.
- the target material may be present between the materials forming the microneedle as being dissolved or dispersed in the microneedle or the materials forming the microneedle may enclose the target material, although not being limited thereto.
- the target material can be administered into the skin regardless of which part of the microneedle it is contained. Even when the target material is contained in a specific zone, even in the rear end of the microneedle, the entire target material may be substantially administered into the skin.
- the microneedle according to the present disclosure may be fabricated according to various methods known in the art. For example, it may be fabricated using the materials, fabrication methods, etc. described in Korean Patent Registration No. 10-0793615 , International Patent Publication No. WO 02/064193 , Korean Patent Publication No. 10-2011-0065361 , etc. More specifically, the microneedle according to the present disclosure may be fabricated through solution casting.
- a mold is prepared first.
- a liquid composition containing a target material is prepared by dissolving the materials constituting the composition and, optionally, dissolving or dispersing the target material.
- the liquid composition containing the target material is added to the mold. Specifically, the mold may be subjected to centrifugation or vacuum treatment so that the target material can be spread deep into the liquid composition. Then, the composition is solidified and then taken out from the mold.
- the present disclosure also provides a soluble microneedle patch containing two or more soluble microneedles and a support holding the soluble microneedles.
- the microneedle patch is also called a microneedle device or a microneedle sheet.
- the microneedle sheet contains one or more microneedle on at least one side of the support and the microneedle can be inserted into the skin by compressing the microneedle sheet.
- a ratio of the soluble microneedle size to the distance between the microneedles may be greater than 0.1 and equal to or smaller than 2, more specifically, 0.5-2. If the ratio is 0.1 or smaller, the amount that can be delivered to the skin is limited because the number of microneedles per unit area is too small. And, if it exceeds 2, the microneedle cannot perforate the skin with the force exerted by a user because the microneedles are arranged too densely.
- the distance between the microneedles refers to the distance between two or more microneedles, which are spaced apart from each other, and can be determined by measuring the linear distance from the tip of one microneedle to the tip of another microneedle.
- microneedle The description about the size of the microneedle is omitted to avoid redundancy because it is the same as defined above.
- the support may be made of the same material as the microneedle and may additionally contain a material having adhesion affinity.
- the material having adhesion affinity may include, for example, an acryl-based or rubber-based adhesive such as polyurethane, polyethylene, polyester, polypropylene, polyvinyl chloride, etc. or a hydrocolloid wherein hydrophilic hydrocolloid particles are dispersed in a hydrophobic polymer matrix, etc., although not being limited thereto.
- a microneedle according to the present disclosure has appropriate mechanical strength, viscosity and hardness, it can be easily inserted into the skin without change in shape such as bending or breaking and enables efficient skin perforation.
- the microneedle according to the present disclosure is dissolved in the perforated skin and exhibits superior skin permeation rate of the material, there is no need of applying strong force and the target material can be effectively delivered into the skin regardless of which part of the microneedle it is contained.
- a microneedle was fabricated as described in Table 1. In the present disclosure, the contents are in wt% units unless specified otherwise.
- a solution was prepared by dissolving HA (hyaluronic acid), Na-CMC (sodium carboxymethyl cellulose) and trehalose in purified water and then adding glycerin, HCO-40 and niacinamide.
- the prepared solution was cast in a silicone microneedle mold and then centrifuged at 3000 rpm for 10 minutes. The resulting solution was filled in a microneedle mold.
- the soluble microneedle was attached to pig skin and the skin was perforated by compressing for 10 seconds with 30 N/cm 2 (exerted by a user). Then, the microneedle was removed immediately. The pig skin was stained with a trypan blue solution and the solution adhering to the surface was wiped with a swab. Then, the hole formed by the microneedle was observed with an optical microscope.
- Test Examples 1-5 showed high skin perforation rates, whereas Comparative Example 1, Comparative Example 2-1 and Comparative Example 3-2 showed very low skin perforation rates of 3%, 5% and 4%, respectively.
- the compressive yield strength of the soluble microneedle was measured using a texture analyzer.
- Test Example 1 showed a compressive yield strength of 1,500 kN/cm 2 ( FIG. 5 ).
- Compressive yield strength kN / cm 2 compressive force / area of microneedle tip
- a drug release behavior was conducted using a Franz diffusion cell ( FIG. 6 ) by measuring the content of a drug (niacinamide) in an acceptor solution with time by liquid chromatography.
- a drug niacinamide
- Skin permeation rate % amount permeated into skin / amount filled in microneedle x 100
- the amount permeated into the skin corresponds to the sum of the drug content in the pig skin tissue and the drug content in the acceptor solution.
- Test Example 1 showed fast increase in the skin permeation rate with time, whereas Comparative Example 1, Comparative Example 2-1 and Comparative Example 3-1 showed little increase of the skin permeation rate of niacinamide. Accordingly, it can be seen that the microneedle according to the test example is more effective in permeating the drug into the skin as compared to the comparative examples.
- the tip diameter, aspect ratio, microneedle density, skin perforation rate, skin permeation rate of the test examples and comparative examples are shown in Table 3.
- Test Examples 1-5 showed high skin perforation rate and, therefore, high skin permeation rate of the drug.
- Comparative Example 1 wherein the tip diameter was 30 ⁇ m, showed very low skin perforation rate. As can be seen from FIG. 8 , the skin permeation rate was very low because the microneedle was bent when compressed.
- Comparative Example 3-1 showed high skin perforation rate, but the skin permeation rate of the drug was low due to low microneedle density.
- Comparative Example 3-2 the microneedle could not easily perforate the skin with the force exerted by a user because the microneedles were arranged too densely and, accordingly, the skin permeation rate was low.
- the present disclosure may provide a microneedle that can be dissolved in skin and a patch product containing the microneedle. Because the microneedle has appropriate mechanical strength, viscosity and hardness, it can be easily inserted into the skin without change in shape such as bending or breaking and enables efficient skin perforation.
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PCT/KR2017/003724 WO2017176045A2 (ko) | 2016-04-05 | 2017-04-05 | 효율적인 피부 천공을 위한 마이크로니들 구조 |
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CN111107897B (zh) * | 2017-09-19 | 2023-05-02 | 株式会社Lg生活健康 | 使用微针贴片的透明质酸填充剂 |
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KR102522220B1 (ko) | 2020-11-18 | 2023-04-14 | 성창규 | 스피룰리나 미셀의 제조방법 및 이를 통해 제조된 스피룰리나 미셀이 탑재된 마이크로니들 |
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KR101224939B1 (ko) | 2009-12-07 | 2013-01-22 | 가천대학교 산학협력단 | 활성 성분의 흡수 속도가 개선된 마이크로니들 |
AU2011246879C1 (en) | 2010-04-28 | 2016-03-24 | Sorrento Therapeutics, Inc. | Device for delivery of rheumatoid arthritis medication |
CN102958555A (zh) * | 2010-04-28 | 2013-03-06 | 金伯利-克拉克环球有限公司 | 注射成型微针阵列和用于形成该微针阵列的方法 |
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EP2785327B1 (de) * | 2011-11-30 | 2023-11-22 | Kindeva Drug Delivery L.P. | Mikronadelvorrichtung, enthaltend ein peptid-therapeutikum und eine aminosäure, herstellungsverfahren und verwendung davon |
WO2013122160A1 (ja) * | 2012-02-17 | 2013-08-22 | コスメディ製薬株式会社 | 短時間溶解型マイクロニードル |
EP4112112A1 (de) * | 2012-05-01 | 2023-01-04 | University of Pittsburgh - Of the Commonwealth System of Higher Education | Spitzenbelastete mikronadelanordnungen zum transdermalen einführen |
ES2743733T3 (es) * | 2012-06-15 | 2020-02-20 | Univ Washington Through Its Center For Commercialization | Dispositivos de cierre de heridas basados en microestructuras |
CN104797287B (zh) * | 2012-11-16 | 2017-12-26 | 3M创新有限公司 | 力控施用装置 |
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-
2016
- 2016-04-05 KR KR1020160041577A patent/KR101719319B1/ko active IP Right Grant
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2017
- 2017-04-05 WO PCT/KR2017/003724 patent/WO2017176045A2/ko active Application Filing
- 2017-04-05 CN CN202210808947.XA patent/CN115068405A/zh active Pending
- 2017-04-05 JP JP2018552670A patent/JP7106186B2/ja active Active
- 2017-04-05 CN CN201780022301.6A patent/CN109069815B/zh active Active
- 2017-04-05 US US16/090,937 patent/US20190117850A1/en not_active Abandoned
- 2017-04-05 EP EP17779345.2A patent/EP3441106B1/de active Active
Also Published As
Publication number | Publication date |
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CN115068405A (zh) | 2022-09-20 |
EP3441106B1 (de) | 2021-01-20 |
JP7106186B2 (ja) | 2022-07-26 |
WO2017176045A3 (ko) | 2018-08-02 |
JP2019513459A (ja) | 2019-05-30 |
EP3441106A4 (de) | 2020-01-01 |
WO2017176045A2 (ko) | 2017-10-12 |
KR101719319B1 (ko) | 2017-03-23 |
CN109069815A (zh) | 2018-12-21 |
CN109069815B (zh) | 2022-08-05 |
US20190117850A1 (en) | 2019-04-25 |
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